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British Journal of Nutrition (2018), 120, 1149–1158 doi:10.1017/S0007114518002684
© The Authors. 2018 This is an Open Access article, distributed under the terms of the Creative Commons Attribution licence (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the
original work is properly cited.

Energy restriction in renal protection

Si-Yang Wang, Guang-Yan Cai* and Xiang-Mei Chen


State Key Laboratory of Kidney Diseases, Department of Nephrology, National Clinical Research Center for Kidney Diseases,
Chinese PLA Institute of Nephrology, Chinese PLA General Hospital, Beijing 100853, People’s Republic of China
(Submitted 23 December 2017 – Final revision received 22 July 2018 – Accepted 20 August 2018)

Abstract
Energy restriction (ER) has been widely studied as a novel intervention, and its ability to prolong life has been fully demonstrated. For
example, ER can significantly extend the lifespans of model flies, worms, rodents and other mammals. The role of ER in renal protection has
also been elucidated. In preclinical studies, adjusting total energy intake or consumption of specific nutrients has prophylactic or therapeutic
effects on ageing-related kidney disease and acute and chronic kidney injury. Amino acid restriction has gradually attracted attention. ER
mimetics have also been studied in depth. The protective mechanisms of ER and ER mimetics for renal injury include increasing AMP-activated
protein kinase and sirtuin type 1 (Sirt1) levels and autophagy and reducing mammalian target of rapamycin, inflammation and oxidative stress.
However, the renal protective effect of ER has mostly been investigated in rodent models, and the role of ER in patients cannot be determined
due to the lack of large randomised controlled trials. To protect the kidney, the mechanism of ER must be thoroughly researched, and more
accurate diet or drug interventions need to be identified.

Key words: Energy restriction: Kidney injury: Ageing: Inflammation: Oxidative stress: Sirtuin type 1: Autophagy

In 1935, McCay et al.(1) discovered for the first time that energy quarter of patients during the first 7 d after intensive care unit
restriction (ER) was able to extend the mean and maximal life- admission(5). These analyses have raised awareness of AKI
spans of rodents. Recently, in a 20-year study of primates, Colman among the public, government officials and health care pro-
found that ER beneficially aided resistance to age-related diseases fessionals. If effective treatment is not provided promptly, AKI
and death(2). ER can ameliorate the effects of senescence and age- will eventually lead to death or CKD. Age is also an important
related diseases without causing malnutrition in many animal risk factor for kidney injury. Therefore, finding a way to delay
models, including invertebrates, rodents and primates. At the same ageing of the kidney and to protect the kidney may have great
time, reducing intake of specific nutrients rather than overall significance for reducing the occurrence of kidney injury.
energy content can also play a key role in these observed effects. Nadon’s study found that ER can prevent or delay the occur-
Restricting protein and specific amino acids largely contributes to rence of age-related nephropathy(6). ER also reduces mesangial
the effects of ER. In addition, the use of energy restriction mimetics cell proliferation, stromal hyperplasia and proteinuria and pre-
(ERM) has gradually gained attention. vent age-related glomerulosclerosis in aged rats(7). The same
Acute kidney injury (AKI) is a common disorder with a high preventive or protective effects against acute and chronic kidney
risk of mortality and development of chronic kidney disease injury are achieved by adjusting total dietary energy content or
(CKD). In 2013, the International Society of Nephrology laun- the ingestion of specific nutritional components. For example,
ched a global target of ‘0by25’ – no patient deaths due to protein restriction (PR) in the diet can improve symptoms of
untreated acute kidney failure by 2025 – to improve the diag- uraemia. In addition, a low-protein diet (plus essential amino
nosis and treatment of AKI globally(3). A systematic review acids or keto acids) can improve metabolic disorders in CKD and
(2004–2012) of large cohort studies published in 2013 on the rectify metabolic acidosis, Ca and P metabolism and other
worldwide AKI prevalence reported that one in five adults and abnormalities, thereby delaying the time of renal replacement
one in three children experienced AKI during a hospital epi- therapy; this diet is therefore an important intervention for the
sode of care(4). Moreover, a recent large, prospective, multi- treatment of CKD. However, the protective effect and mechan-
national study of AKI epidemiology in children and young ism of ER in renal injury have not been fully elucidated. In this
adults in intensive care units showed that AKI occurred in one- review, we summarise the current knowledge in this regard.

Abbreviations: AKI, acute kidney injury; AMPK, AMP-activated protein kinase; CKD, chronic kidney disease; DN, diabetic nephropathy; ER, energy restriction;
ERM, energy restriction mimetics; ESRD, end-stage renal disease; HIF, hypoxia-inducible factor 1; mTOR, mammalian target of rapamycin; Pi, inorganic
phosphate; PR, protein restriction; ROS, reactive oxygen species; Sirt1, sirtuin type 1; TGF-β, transforming growth factor-β.
* Corresponding author: Dr G.-Y. Cai, fax +86 10 6813 0297, email caiguangyan@sina.com
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1150 S.-Y. Wang et al.

In some studies, dietary restriction (DR) is equivalent to ER, disease. The AMP-activated protein kinase (AMPK) and mam-
indicating an overall decrease in food consumption. Most DR malian target of rapamycin (mTOR) pathways are important for
studies impose a 20–40 % ER, and the duration of this restriction cellular energy metabolism. Increased mTOR expression in the
ranges from a few weeks to an entire lifespan(8). After the ageing kidneys of rats indicates that mTOR activation can
beneficial effects of ER on the body were confirmed by a large accelerate senescence of the kidney(13), whereas AMPK phos-
number of studies, questions arose concerning whether the phorylation can inhibit this process. Mammalian target of
reduced intake of certain nutrients, such as proteins, lipids or rapamycin complex 1 (mTORC1) inhibition in aged rats can
carbohydrates, induced by ER played a synergistic role in the regulate age-related gene changes in the kidney and block age-
body. Although some studies have found that restricting car- related chronic progressive nephropathy(14). Our previous
bohydrates, lipids, minerals and other nutrients does not sig- study also found that stimulation with high glucose induced
nificantly extend lifespan, inhibit tumour development or senescence in rat mesangial cells through AMPK/mTOR path-
impose other effects(9,10), most PR studies have reported long- ways(15). Our later study showed that short-term ER directly up-
evity benefits. These findings highlighted the specific impor- regulated AMPK and down-regulated the mTOR signalling path-
tance of PR, even though the effect of PR was less than that of way, which significantly down-regulated urinary proteins in older
ER(11). Next, researchers began to explore whether the restric- rats and delayed tubular epithelial cell senescence and the epi-
tion of a particular amino acid was responsible for the main thelial to mesenchymal transition (EMT) stimulated by high glu-
benefit of PR(12). cose(16). MicroRNA-21 (miR-21) targets the regulation of PPARα,
which can promote the EMT in human renal tubular epithelial cells
through hypoxia-inducible factor (HIF)-1α(17). In rats, long-term ER
Basic study and mechanisms significantly improves ageing and fibrosis of the kidneys and
reduces miR-21 expression in ageing renal tissue or urinary exo-
To observe the effects of ER on the lifespan and kidney disease,
somes. A meta-analysis of ER studies revealed that ER delayed the
studies have focused on basic research with animal models. The
progression of CKD, reduced serum creatinine, urea N and pro-
identified mechanisms include increased autophagy, reduced
teinuria levels and improved the survival rate in rodent models by
inflammation and oxidative stress, improved insulin sensitivity
reducing the incidence of diseases, such as CKD(8).
and increased sirtuin type 1 (Sirt1) levels (Fig. 1). The amount
Lopez-Dominguez et al. studied the effect of fat composition
(20–40 %) and duration (intermittent or continuous fasting ran-
on longevity. The mice were divided into a control group and
ging from weeks to the entire lifespan) of ER also vary.
three 40 % ER groups. The fat sources of the three ER groups
were soyabean oil (high in n-6 PUFA), fish oil (high in n-3
Ageing-related renal changes PUFA) or lard (high in SFA and MUFA). This study found that
the animals fed lard had increased longevity compared with the
In ER studies, effects on ageing and ageing-related alterations mice fed soyabean or fish oil(18). This finding suggests that the
are the primary observational indicators, and these parameters use of a low proportion of PUFA and a high proportion of
have been used in various animal models, including humans, MUFA and SFA can maximise the lifespan under ER conditions.
mice, flies and worms. Currently, most studies on kidney Using a ER model, Calvo-Rubio et al. studied the contribution of
senescence use rodent or primate models. Many studies have fat sources to changes in the kidney structure. Long-term ER
shown that ER can delay the ageing-induced incidence of CKD, improved the structure of senescent kidneys, as evidenced by
improve kidney function and delay the incidence of kidney the enlargement of the glomerular basal membrane (GBM) and
podocyte foot processes (PFP), narrowing of the filtration slits
Dietary intervention and modification of proximal convoluted tubule cells. In addi-
tion, the beneficial effects of ER on GBM thickness, PFP width,
Protein restriction autophagy and the mitochondrial mass, size and shape were
Energy restriction
based on lard as the main fat source(19). This result clarifies the
Energy restriction mimetics
SAA (H2S) BCAA
critical role of fat sources in delaying kidney ageing.
Metformin Rapamycin Resveratrol

Inflammation
AMPK mTOR AMPK/mTOR Sirt1/autophagy
Sirt1 Inflammation
Autophagy Oxidative stress
During ageing, inflammation and proinflammatory factors gra-
… … dually increase, which is called the senescence-associated
secretory phenotype (SASP). In addition, chronic inflammation
is considered a potential risk factor for senescence(20,21). Inhi-
biting inflammation may be an important strategy to slow age-
Kidney injury/senescence ing. In mice, chronic inflammation induced by selective
knockout of the NF-κB subunit leads to premature ageing via
Fig. 1. The mechanisms of energy restriction in renal protection. The main reactive oxygen species (ROS)-mediated exacerbation of telo-
identified mechanisms include increased AMP-activated protein kinase
mere dysfunction and cell senescence(22). Some studies have
(AMPK), sirtuin type 1 (Sirt1) and autophagy and reduced mammalian target
of rapamycin (mTOR), inflammation and oxidative stress. SAA, sulphur amino revealed that SASP reinforces senescence via increasing ROS in
acid; BCAA, branched-chain amino acid. a mechanism similar to interferon-β and transforming growth
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Energy restriction in renal protection 1151

factor-β (TGF-β)(23,24). End-stage renal disease (ESRD) patients reperfusion injury in the liver and kidney via endogenous H2S
have an abnormal immune system. Uraemic inflammation is levels(37). SAA restriction reduces mitochondrial oxidative stress in
related to mechanisms involved in the ageing process, such as the brain, heart, liver and kidneys(38–40). Our previous studies
telomere shortening, mitochondrial dysfunction and altered discovered that the production of endogenous H2S was up-
nutrient sensing. These mechanisms may promote a premature regulated after exposure of ageing male F344 rats to 30 % ER,
ageing process of the uraemic immune system(25). which resulted in decreased ROS levels, protein carbonylation and
In animals, ER can reduce the level of inflammatory cytokines malondialdehyde production; in addition, the redox balance was
and mitigate inflammation. The NF-κB transcription and proin- maintained, and kidney ageing was delayed. Furthermore, differ-
flammatory cytokine levels increase with age(26). During the ent durations of ER had different protective effects against oxida-
renal senescence process, IL-1β and IL-18 promote apoptosis in tive stress in ageing kidneys. Compared with short-term (6 weeks)
mesangial cells and podocytes, facilitate extracellular matrix ER, ER lasting 6 months or the entire lifespan significantly pro-
deposition and eventually lead to glomerulosclerosis(27). A longed the lifespan and reduced oxidative stress(41).
6-week ER can reduce TNF-α expression in the rat liver(28).
Short-term (4 weeks) ER also reduces expression of a variety of
Sirtuin type 1 and autophagy
inflammatory factors, improves insulin sensitivity and ultimately
relieves renal ischaemia–reperfusion injury. These effects con- Initially, Sirt1 was identified as a NAD-dependent histone dea-
tribute to an increased survival rate(29). Pathological studies cetylase(42). Subsequent studies have shown that under fasting
have also shown that ER can reduce a variety of glomerular and conditions, Sirt1 regulates energy metabolism and the stress
tubular injuries, including proliferation in ageing kidneys, leu- response via acetylation of many internal nuclear transcription
kocyte infiltration, vascular endothelial thickening, thrombosis, factors(43). In addition, some studies have demonstrated an
interstitial inflammatory cell infiltration and epithelial cell effect of ER and Sirt1 on kidney injury and glomerular diseases
degeneration, atrophy and interstitial fibrosis. ER blocks the Toll- in ageing models. Research on the protective mechanism of
like receptor 4 (TLR4)/NF-κB signalling pathway by over- Sirt1 in the kidney under ER conditions is gradually expanding.
expressing the single Ig IL-1-related molecule (SIGIRR), thereby Sirt1 is mainly expressed in renal tubules. In mice, Sirt1
reducing the expression of downstream inflammatory cytokines activity gradually decreases with age in the kidney and in a
and slowing inflammation of the kidney(30). SIGIRR negatively mouse model of diabetic nephropathy (DN), but this effect can
regulates the TLR4 signalling pathway, inhibits lipopolysaccharide- be reversed by ER(44). Compared with the levels in younger
induced activation of TLR4 and NF-κB and down-regulates animals, 24-month-old mice presented with decreased Sirt1
expression of leukocyte adhesion molecules, cytokines and expression, increased mitochondrial oxidative stress and
angiogenic factors(31). SIGIRR is an important negative regulator of abnormal mitochondrial morphology in the kidney. Beginning a
inflammation(32) that can inhibit renal fibrosis(33). The specific 40 % ER intervention at 12 months of age can relieve the ageing-
mechanism of ER and inflammation in the ageing kidney has yet associated changes observed in mice(45). Long-term ER
to be fully elucidated; therefore, SIGIRR may be an important improves autophagic activity, which also occurs in ageing kid-
component in the ER-induced anti-inflammatory anti-ageing pro- neys. Autophagy provides nutrients and energy by degrading
cess and may serve as a new target for slowing ageing. unessential contents within the autophagosome. This process
can also prevent cell damage and cell apoptosis by degrading
potential toxic proteins(46). Autophagy activation has been
Oxidative stress
found to be essential for ER-mediated life extension and anti-
ROS and other active molecules are produced in excess when the ageing effects in both lower animal species and mammals.
body continues to encounter stress factors. The oxidative and Short-term ER activates autophagy in renal tubular epithelial
antioxidative systems become unbalanced. This imbalance can be cells(45). In addition, long-term ER in ageing rats significantly
further aggravated if the body presents with additional defects in improves autophagy and reduces DNA damage and ageing
the antioxidant capacity, eventually leading to injury(34,35). There- markers(47). Sirt1-mediated autophagy may be critical for the
fore, to delay kidney ageing and prevent and treat ageing-related mechanisms of ER. BCL2/adenovirus E1B 19 kDa protein-
kidney disease, the level of oxidative stress in the body must be interacting protein 3 (Bnip3) is a gene that activates autophagy.
reduced, and the redox balance should be maintained. In Sirt1+ / − kidneys, autophagic activity is low, and Bnip3
D-β-Hydroxybutyrate (βOHB) is an endogenous specific expression is decreased; however, ER activates Sirt1 and
inhibitor of class I histone deacetylases. In addition to admin- FOXO3a transcription and Bnip3-mediated autophagy. The
istration of exogenous βOHB, fasting and ER can increase the sequestosome 1 (p62/Sqstm1) pathway is involved in autop-
production of endogenous βOHB, resulting in histone acetyla- hagy; ER increases p62/Sqstm1 signalling, improves the func-
tion in mouse tissues and transcription of antioxidant stress tion of the autophagy system and normalises mitochondrial
factors, such as Forkhead box O3 (Foxo3a) and metallothio- morphology in addition to rescuing Sirt1 expression(44).
nein-2(36). The most recent literature shows that ER suppresses In a kidney disease model, Sirt1 activation attenuates cisplatin-
mitochondrial oxidative stress by up-regulating H2S production, induced renal tubular injury. The molecular mechanisms involve
which protects the liver and kidneys from ischaemia–reperfu- inactivating core histone transcription and repairing DNA
sion injury. Further in vivo and in vitro experiments have damage(48). An 8-week ER increases Sirt1 expression in the kid-
shown that restricting the intake of sulphur amino acids (SAA), neys of aged rats, inhibits renal tubular epithelial cell apoptosis
such as cysteine and methionine, can also mitigate ischaemia– and reduces cisplatin-induced AKI(49). Microinflammation has
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1152 S.-Y. Wang et al.

recently been implicated in the pathogenesis of or treatment for balance. Methionine and cysteine supplementation abrogated
DN. Sirt1 also has anti-inflammatory effects in many organs(50), H2S production and the significant benefits of combined protein/
suggesting that Sirt1 is involved in ER-related anti-inflammatory energy restriction(37). This finding provides a new mechanism for
molecular mechanisms. Moreover, Sirt1 up-regulates cyclo-oxy- the protective effect of methionine restriction. Although toxic at
genase-2 expression in the kidney by interfering with HIF-2α high levels, H2S is produced at low concentrations due to
activation, increases peroxidase activity and inhibits the expression cysteine or homocysteine degradation by CGL and has a bene-
of TGF-β-Smad3 (mothers against decapentaplegic homolog 3), ficial effect on the vasculature and brain. H2S acts as a signalling
NF-κB, p53 and other pathways to prevent inflammation, apop- molecule to reduce blood pressure(60) and prevent neurode-
tosis, fibrosis and proliferation in the kidney(51). generation(61). Exogenous H2S can also extend the lifespan of
worms(62) and induce suspended animation-like states in mam-
mals(63). The increase in H2S production induced by SAA
restriction can activate the proangiogenic pathway through
Protein restriction
general control non-derepressible 2/activating transcription fac-
A large number of studies have proven the protective effect of tor 4 (GCN2-/ATF4) in endothelial cells, which increases capil-
ER, but it remains unclear whether a specific nutrient in the diet lary density in mouse skeletal muscle(64). In addition, an
mediates the main effect of ER. After comparing multiple interaction occurs between H2S and Sirt1 during regulation of
nutrients, PR has emerged as potentially important for ER(11). angiogenesis in old mice to reverse age-associated loss in muscle
Studies have shown that PR can achieve effects similar to vascular density. H2S has been hypothesised to delay ageing in
those of ER. FOXO3, hepatocyte nuclear factor 4 and high part by activating Sirt1, which is a major lifespan regulator(65). As
mobility group A1 expression in the kidneys of 3-month-old the only source of endogenous H2S, methionine restriction may
male C57 mice was increased by 30 % ER and 3-d PR, thereby have a good application prospect for renal protection.
reducing ischaemia–reperfusion injury in the kidney(52). In Dahl Leucine restriction (LR) for 7 d resulted in body weight loss
SS rats, a high-protein diet exacerbates the deterioration in and decreased adiposity(66). A specific reduction in the con-
blood pressure that accompanies extensive glomerular inflam- sumption of three branched-chain amino acids (BCAA; leucine,
matory cell infiltration(53). PR also has an effect on the mTOR isoleucine and valine) by mice can improve metabolic
pathway that is similar to that of ER. In male mice, PR and ER health(67). LR can replicate some, but not all of the effects of
both contribute to the benefits of short-term ER against renal methionine restriction, such as decreasing body and fat mass,
ischaemic–reperfusion injury in a manner that is partially elevating lipid cycling in white adipose tissue and improving
dependent on AMPK activation and mTORC1 repression(54). As whole-body glucose metabolism and hepatic insulin sensitiv-
a nutrient-associated pathway, AMPK/mTOR plays a key role in ity(68). However, changes in the kidney after LR have not been
the protective effect in the kidney during PR or ER(54), and investigated. Insulin resistance affects many aspects of kidney
mTOR has been shown to be a central regulator of cell growth. function, including renal haemodynamics, podocyte viability
mTOR activation plays a pivotal role in DN and the develop- and tubular function(69). Thus, BCAA restriction may be a pro-
ment of ESRD(55). Thus, inhibition of mTOR may be a strong mising treatment for DN in addition to LR.
potential therapeutic target for acute and chronic kidney injury. In CKD, PR can reduce proteinuria and decrease urea N
Regarding specific amino acids, methionine restriction levels and changes in the kidney; however, excessive PR
achieves effects similar to those of PR, such as reducing mito- decreases the serum albumin level and slows growth. Adding
chondrial ROS production, free radical leakage and the mito- keto acids can correct these results and have better effects than
chondrial DNA 8-oxo-2′-deoxyguanosine levels(11). Chronic or single PR(70). Kruppel-like factor 15 (KLF15) is a transcription
excessive methionine supplementation also increases renal factor that is reduced in heart fibrosis. KLF15 was also
tubulointerstitial damage(56). In the rat liver and kidney, decreased in a CKD model. PR increases the KLF15 level in
methionine supplementation increases the two methionine- healthy kidneys and partially recovers the KLF15 level in kid-
derived circulating metabolites (S-adenosylmethionine (SAM) neys with residual renal function(71). This finding demonstrates
and S-adenosine homocysteine (SAH)) and induces some the potential role of PR in anti-renal fibrosis.
damage, such as the generation of mitochondrial free radicals
and oxidative DNA damage. Mitochondrial and DNA damage
are related to overproduction of SAM and SAH(57). A 40 % Energy restriction mimetics
methionine restriction reduces mitochondrial ROS production,
Metformin
free radical release, renal mitochondrial DNA oxidative damage
and mitochondrial protein oxidation-specific markers (i.e. ERM are drugs that increase the consumption of food and water
lipoxidation and glycoxidation). This methionine restriction also without adjusting energy intake and are believed to achieve the
reduces the expression levels of mitochondrial respiratory chain same effects as ER, such as prolonging the lifespan and redu-
complexes I, III and IV, apoptosis-inducing factor and renal cing age-related diseases(72). Metformin is a representative
mitochondrial complex IV in the brain(58,59). In 2015, Hine et al. ERM drug.
found that ER increased production of endogenous H2S in the Derivatives of biguanide compounds, such as buformin,
liver and kidney through increased synthase cystathionine-γ- metformin and phenformin, improve the stability of blood
lyase (CGL) and cystathionine-β-synthase expression, which glucose and demonstrate preventive effects on ageing. These
reduced ischaemia–reperfusion injury by restoring the redox drugs can also induce metabolic effects by activating AMPK and
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Energy restriction in renal protection 1153

inhibiting mTOR(73). Metformin slows ageing and extends the metanephric cultures(83). Due to its outstanding effect on
lifespan of female spontaneously hypertensive rat mice(74). In mTOR inhibition, rapamycin may have a good application
addition, metformin impedes the TGF-β-induced loss of the prospect for kidney disease, especially DN and ADPKD.
epithelial marker E-cadherin in MCF-7 breast cancer cells and
prevents the accumulation of the mesenchymal marker
Resveratrol
vimentin in Madin–Darby canine kidney (MDCK) cells(75). In
Zucker diabetic fatty rats, metformin decreases oxygen con- Resveratrol, which is a monomer of polyphenol found in
sumption and the ATP levels, increases the intracellular oxygen grapes, can also simulate the biological effects produced by ER,
partial pressure and reduces HIF-1 expression, pimonidazole such as reducing oxidative stress in renal injury. Recent studies
staining and renal damage(76). In our experiments, metformin by Kitada have shown that resveratrol can inhibit Smad3 acet-
inhibited the expression of HIF-1α and its target genes in human ylation by activating Sirt1 in unilateral ureteral obstruction
renal proximal tubular epithelial cells(16). Studies on the renal- (UUO) animal models or cultured cells, leading to a decrease in
protective effects of metformin have mainly been conducted TGF-β1-induced type IV collagen and fibronectin. This effect
with diabetic patients. A recent systematic review showed that can alleviate renal injury during hypoxic stress(84). Resveratrol
metformin reduced the all-cause death rate in diabetic patients can also improve the activity and function of antioxidants by
with CKD (glomerular filtration rate (GFR) <60 ml/min per activating Sirt1 during acute and chronic kidney injury(85). For
1·73 m2)(77). However, the application of this result in patients AKI models, resveratrol can be used from 10 to 100 mg/kg and
with DN is limited, since they are at risk for lactic acidosis. the protective effects can be produced within 3–5 d of injec-
Because the clinical application of metformin is still mainly tion(86–88). This shows that resveratrol can have the effect on
focused on the treatment of diabetes mellitus, the effects of renal protection in a short time. However, the long-term effect
metformin on other diseases, such as cancer and lifespan, of resveratrol on the renal repair function after AKI is relatively
remain controversial. The US National Institute on Aging limited, and can be one of the research directions in the future.
Interventions Testing Program(78) evaluated the influence of The beneficial effects of ER involve impacts on the function of
different agents on longevity in genetically heterogeneous mice. Sirt1. Sirt1 is a key molecule that regulates renal protective effects
When used alone, metformin showed a non-significant effect in various renal disorder models. The protective effects include
on the median lifespan, and the site-specific effects were maintenance of glomerular barrier function, anti-fibrotic effects,
indistinguishable from chance, which was different from some anti-oxidative stress effects and regulation of mitochondrial
past reports. This discrepancy was likely due to the use of function and energy metabolism(89). Resveratrol is the most
genetically heterogeneous mice, the initiation time of metformin potent Sirt1 activator. Sirt1 is highly expressed in the kidney,
treatment, evaluation of male and female mice, analysis at three especially in proximal tubular cells. Moreover, renal proximal
independent sites and the choice of statistical method. Inter- tubular cells are susceptible to injury, and senescence may occur
estingly, metformin combined with rapamycin robustly exten- first in tubular cells. These facts all make resveratrol a superior
ded the lifespan, which was an added benefit, compared to ERM for the kidney. In diabetic mouse models, Sirt1 expression is
rapamycin alone, indicating that metformin might have some significantly reduced in the proximal tubules of wild-type
positive effects on the lifespan. However, large-scale clinical mice(89). Previous studies have clearly demonstrated that resver-
trials are needed to evaluate the effects on longevity and renal atrol can improve DN in several animal models of type 1 and
disease patients. 2 diabetes. Resveratrol prevents DN in db/db mice by phos-
phorylation of AMPK and activation of Sirt1 to prevent mesangial
cell apoptosis and oxidative stress in the kidney(90). Therefore,
Rapamycin
resveratrol may have a protective effect on both AKI and CKD.
Rapamycin is an Food and Drug Administration-approved The effect of resveratrol may be mediated through a Sirt1-
drug that is used to coat coronary stents and prevent organ independent mechanism. The mTOR signalling pathway is
transplant rejection, such as kidney and islets(79). Rapamycin associated with DN and polycystic kidney disease(91,92). Resver-
specifically inhibits mTOR and leads to very significant inhi- atrol increases the interaction between mTOR and its inhibitor
bition of renal cyst growth as a ERM for renal protection. DEP (dishevelled, egl-10, pleckstrin) domain-containing mTOR-
Autophagy is regulated by mTORC1 and other nutrient- interacting protein, resulting in mTOR inhibition(93). Therefore,
responsive intracellular signals; rapamycin, which improves resveratrol may also achieve its renal protective effect through
glomerular lesions in experimental DN, can activate autop- mTOR. Our study also found that resveratrol mitigated high
hagy(80). Autosomal-dominant polycystic kidney disease glucose-induced human proximal tubular cell senescence
(ADPKD) is a common cause of ESRD. The mTOR pathway in vitro and prevented the formation of paracrine vesicles con-
has been shown to be activated in ADPKD, and inhibition of taining miR-21, which promoted the EMT process(16).
mTOR with rapamycin decreases the development of ADPKD
in mice(81,82). In diabetic obese db/db mice, which are char-
acterised by mTOR activation, systemic administration of Clinical studies
rapamycin markedly ameliorates pathological changes and
Energy content and proteins
renal dysfunctions(55). Inhibition of the mTOR pathway with
rapamycin and activation of the AMPK pathway with metfor- Clinical studies on ER have focused on metabolism and insulin
min also lead to decreased cystogenesis in MDCK cell and sensitivity as well as oxidative stress, inflammation,
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1154 S.-Y. Wang et al.

cardiovascular risk factors and corresponding indicators of research results related to PR are inconsistent. Some studies
patients with obesity or diabetes. Clinical studies on the renal- indicate that changes in protein intake will not cause significant
protective effects are more concentrated on PR in CKD patients changes in renal function, disease progression or the risk of
and on ER in DN patients. dialysis and death(104–106). However, most studies show that PR
Clinical studies on ER are limited, and thus the role of ER in delays the decline in renal function and improves the renal
CKD patients cannot be determined due to the lack of large survival rate. Although the results vary, they still support dietary
randomised controlled trials (RCT). Giordani et al.(94) analysed intervention for patients with early CKD and DN.
the glomerular filtration rate (GFR) of fourteen obese patients
with type 2 diabetes and stage 2 CKD; the study concluded that
Salt
7 d of a low-energy diet significantly improved the GFR of these
patients. Therefore, short-term ER may improve renal function. Urinary albumin excretion is an important independent risk factor
In addition, ER for 12 weeks decreased body weight and the for the development and progression of kidney disease as well as
serum creatinine and cystatin C levels in obese patients with DN for CVD, such as diabetes and hypertension. A number of RCT
and increased the GFR(95). In 2003, Morales et al.(96) studied the studies have shown that limiting salt intake significantly reduces
weights and proteinuria of CKD patients. A total of thirty urinary albumin and the albumin:creatinine ratio (9·1 mg/24 h and
overweight or obese patients with albuminuria, including DN 0·66 mg/mmol, respectively) and improves arterial compliance in
patients and patients with other manifestations of proteinuria, different ethnic patients with mild hypertension(107). In CKD
were randomly divided into two groups. The patients were patients with proteinuria, salt restriction reduces the vascular
given either a normal diet or a low-energy diet. After 5 months, endothelial growth factor C and N terminal pro B type natriuretic
the urine protein was decreased by 30 % in the ER group (from peptide levels, impairs increases in the extracellular volume and
an average of 2·8–1·9 g/d). The renal function remained stable decreases hypertension(108). In patients with high blood pressure,
in the ER group but had a worsening trend in the free diet urine protein can be reduced from 93 (SD 48) to 75 (SD 30) mg/
group; however, the renal function was not significantly dif- 24 h(109). However, endpoint events were not observed. In 2015,
ferent between the two groups. McMahon et al.(110) conducted a systematic analysis of eight pre-
Ageing progresses so slowly that clinical dietary interventions vious studies and found a lack of evidence supporting the long-
on ageing take a very long time and may be difficult to apply in term effects of low salt intake in CKD patients and the direct
people due to inconvenience issues. In addition, ER may still impact of this modification on end points such as mortality and
cause some negative effects, such as a decline in the quality of life, ESRD. A decrease in blood pressure and proteinuria was identi-
and people may not adhere to long-term ER. Although ER has fied, which was beneficial for reducing the incidence of ESRD and
proven to be beneficial for longevity in animal models ranging cardiovascular events in CKD patients.
from worms to primates, long-term ER is difficult to achieve in
people. For people, ERM may be more practical than ER(97).
Phosphorus
The PR program for kidney disease may have been per-
formed for the first time in patients by Kempner(98). Kempner Hyperphosphataemia accelerates renal failure. Moreover,
thought that the kidney played a key role in malignant hyper- accelerated ageing is associated with high serum inorganic
tension. He began to treat patients with malignant hypertension phosphate (Pi) levels. The Psychological, Social and Biological
with a diet composed of nothing but rice and fruit. Most patients Determinants of Ill Health pSoBid cohort study performed by
were able to reduce their blood pressure. However, he also the University of Glasgow explored the impact of dietary P
found that the treatment of kidney disease and hypertensive intake on human age-related health. The data indicate that high
with the rice diet was either ineffective or dangerous unless it Pi levels are associated with features of biological ageing, such
was conducted under rigidly controlled conditions(99). There- as decreasing telomere lengths and increases in inflammation
fore, the time and level of PR are essential for the regimen for and DNA hypomethylation. For renal health, Pi levels have a
renal disease patients. PR reduces uraemic toxins, blood urea N close relationship with renal function based on estimated glo-
levels, the acid load, oxidative stress and the phosphate load merular filtration rate (eGFR) measurement. Some subjects with
and also improves insulin resistance and control over metabolic high Pi levels have eGFR values indicative of incipient or early
bone disease and ameliorates anaemia(100–103). Depending on onset CKD(111). Pi overload may lead to tubular injury and
the protein source, PR may delay progression of CKD mainly by interstitial fibrosis(112). Serum phosphate and its product, cal-
reducing the Na, K and P levels. Adding keto acids to PR during cium phosphate, were increased significantly in uraemic rats
CKD stages 4–5 or before or during dialysis aids in the avoid- fed high P for 6 months, resulting in a mortality rate of 71·4 %. In
ance of malnutrition and improves the patient prognosis. rats fed a low-P diet, the parathyroid hormone and fibroblast
Although this method improves endothelial function, no growth factor-23 (FGF-23) levels were significantly decreased in
obvious reduction in cardiovascular risk has been found(70). PR the blood, and the mortality rate was only 5·9 %. In addition to
did not significantly decrease blood P levels, and a vegetarian reducing vascular calcification, a low-P diet can relieve renal
diet only reduced blood P by 3 mg/l. The modification of diet in interstitial fibrosis, glomerular sclerosis and inflammatory cell
renal disease study also showed that the risk of death for infiltration(113). High levels of hyperphosphataemia are asso-
patients with advanced CKD receiving a very low-protein diet ciated with CVD events in CKD and ESRD populations as well
of 0·58 g/kg body weight per d was higher than that for patients as in healthy people. In dialysis patients, high P and death are
receiving a low-protein diet of 0·6–0·8 g/kg per d. The clinical positively correlated. FGF-23 is the most important P-regulating
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Energy restriction in renal protection 1155

hormone and increases P excretion when the serum phosphate Acknowledgements


level is too high, but FGF-23 also decreases the vitamin D levels,
This work was supported by the National Key R&D Program of
promotes ventricular hypertrophy, accelerates the deterioration
China (2018YFA0108803), the 973 Program (2013CB530800), the
of renal function and increases cardiovascular mortality.
Twelfth Five-Year National Key Technology Research and Devel-
Dietary P includes both organic and inorganic P. Organic
opment Program (2015BAI12B06 and 2013BAI09B05), the 863
P comes from protein sources, whereas inorganic P originates
Program (2012AA02A512) and the NSFC (81401160 and 81070267).
from additives or preservatives. Although the body absorbs
W.-S. Y. contributed to the literature search and analysis of
approximately 90 % of inorganic P, the absorption of organic
the published data. W.-S. Y., C.-G. Y. and C.-X. M. contributed
P is only 40–60 %(114). In an effort to limit P, PR may increase the
to the manuscript writing and revisions of the article. All authors
incidence of mortality and malnutrition in CKD and dialysis
approved the final manuscript.
patients. The Kidney Disease Outcomes Quality Initiative
The authors declare no conflicts of interest arising from the
recommends a P intake of 800–1000 mg/d for CKD patients(115).
conclusions of this work.
Selamet et al.(116) found that phosphates in food were not
associated with the incidence of ESRD or CVD or with non-CVD
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